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. 2020 Sep 2:16:2141-2150.
doi: 10.3762/bjoc.16.182. eCollection 2020.

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Benjamin Jeffries  1 , Zhong Wang  1 , Robert I Troup  1 , Anaïs Goupille  2 , Jean-Yves Le Questel  2 , Charlene Fallan  3 , James S Scott  3 , Elisabetta Chiarparin  3 , Jérôme Graton  2 , Bruno Linclau  1
Affiliations

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Benjamin Jeffries et al. Beilstein J Org Chem. .

Abstract

A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

Keywords: aliphatic fluorination; cyclopropane; isopropyl; isostere; lipophilicity; oxetane.

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Figures

Figure 1
Figure 1
Examples of lipophilicity modulation for geminal dimethyl to cyclopropyl and oxetane modifications (measured experimentally via shake-flask method).
Figure 2
Figure 2
Lipophilicity modulation examples involving fluorinated cyclopropane derivatives (measured experimentally via shake-flask method).
Figure 3
Figure 3
Lipophilicity changes upon fluorination of isopropyl, cyclopropane and oxetane rings (Series A, C: measured experimentally via shake-flask method; series B: measured experimentally by reversed-phase HPLC).
Figure 4
Figure 4
Lipophilicity modulations discussed in this contribution.
Figure 5
Figure 5
Distribution of the experimental lipophilicity values of series D, E and F (* denotes an estimated value, see Supporting Information File 1).
Figure 6
Figure 6
Comparison of lipophilicities between the linear alkyl, isopropyl, cyclopropyl, and 3-oxetanyl substituents by fluorination level (exchange two C–H bonds by a C–C bond or C–O–C bonds, same carbon count).
Figure 7
Figure 7
Comparison of lipophilicities between isopropyl and cyclopropyl substituents grouped by exchange of C–H/C–F bonds by a C–C bond (same carbon count). Organised by the exchanged fluorine being the only fluorine substituent on the carbon involved (A) or as part of a CF2 (B) or CF3 (C) group.
Figure 8
Figure 8
Carbon extensions.
Figure 9
Figure 9
Experimental and theoretical (in blue) values (calculated at the MN15/aug-cc-pVTZ//MN15/cc-pVTZ level of theory). Values for G1, G4, G7, G8 taken from the literature [28]. The distance between the lines relate to the relative lipophilicity differences. Experimental and theoretical data sets normalized towards the parent compound.
Figure 10
Figure 10
Correlation of the DFT-calculated lipophilicities with the experimental values. A) fluorinated series D, E, F, G2–4, G7, G8, B) Compilation with other fluorohydrins (taken from reference [28]).
Figure 11
Figure 11
Experimental (in black) and theoretical (in blue) values (calculated at the MN15/aug-cc-pVTZ//MN15/cc-pVTZ level of theory) of all compounds, organized by motif.
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References

    1. Persch E, Dumele O, Diederich F. Angew Chem, Int Ed. 2015;54:3290–3327. doi: 10.1002/anie.201408487. - DOI - PubMed
    1. Mecozzi S, Rebek J., Jr Chem – Eur J. 1998;4:1016–1022. doi: 10.1002/(sici)1521-3765(19980615)4:6<1016::aid-chem1016>3.0.co;2-b. - DOI
    1. Bissantz C, Kuhn B, Stahl M. J Med Chem. 2010;53:5061–5084. doi: 10.1021/jm100112j. - DOI - PMC - PubMed
    1. Zauhar R J, Moyna G, Tian L, Li Z, Welsh W J. J Med Chem. 2003;46:5674–5690. doi: 10.1021/jm030242k. - DOI - PubMed
    1. Kumar A, Zhang K Y J. Front Chem (Lausanne, Switz) 2018;6:315. doi: 10.3389/fchem.2018.00315. - DOI - PMC - PubMed

Grants and funding

We are grateful to AstraZeneca for a CASE award, and to the EPSRC for a CASE Conversion grant (EP/M508147/1), a standard grant (EP/P019943/1), and a core capability grant (EP/K039466/1). The CCIPL (Centre de Calcul Intensif des Pays de Loire) is acknowledged for provision of computer time.

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